In this study, a multifunctional nano-drug (PTX-loaded Cys-FeO/CuS@BSA nanocomposite), which performs well in hydrophobic drug delivery, magnetic resonance imaging (MRI) and chemo-photothermal combination therapy, has been successfully synthesized via a facile method with several biocompatible agents. The characterization verified that our as-obtained nanocarrier has a preferable average diameter of about 300 nm for cancer therapy, shows a great MRI ability and magnetism performance, and exhibits a favorable in vitro and in vivo photothermal therapeutic efficacy by introducing CuS, and the sustained release of chemotherapeutics could be controlled by pH value and near-infrared laser irradiation has further enhanced the therapeutic performance. Overall, the excellent synergistic effect to inhibit tumor growth effectively realized via imaging-guided combinational chemo-photothermal therapy in the present work, highlights the promise of conquering the limitations of tumor treatments.